Biological and Cell Therapies in Orthopaedics - Autologous Chondrocyte and Mesenchymal Stem Cell Implantation
Submitting InstitutionKeele University
Unit of AssessmentGeneral Engineering
Summary Impact TypeTechnological
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology
Engineering: Biomedical Engineering
Medical and Health Sciences: Clinical Sciences
Summary of the impact
A multidisciplinary team has worked in applied cell engineering
implementing cell therapy and biological approaches in clinical practice
since 1997. The team has two GMP accredited laboratories in hospital sites
and a MHRA manufacturing license for chondrocytes and stromal /stem cells
for delivery to patients in orthopaedic clinical trials. The research had
impacts on health, economy, public policy and practitioners. Over 400
cartilage patients and over 150,000 knee ligament patients have benefited
directly from the research, and associated turnover is over £40,000,000.
Team members had influence on government, NICE and professional
With ageing and disease, many musculoskeletal tissues lose the ability to
regenerate and repair, resulting in impaired function and severe pain.
Cartilage deterioration and the development of osteoarthritis form a
pervasive and expensive medical problem. According to the OECD, 10% of men
and 18% of women over 60 have symptomatic osteoarthritis worldwide. Each
year in the OECD, >2.5 million people receive hip replacements and
>1.5 million people knee replacements. Increasingly, the health care
industry needs low-cost alternatives to treat a growing elderly population
susceptible. Finding a safe, effective and enduring solution for millions
of people suffering from cartilage deterioration represents an unmet
medical need. Developing the clinical science to treat these defects with
cell therapy required a multidisciplinary team with underpinning science,
clinical and manufacturing disciplines. Whilst our underpinning research
has covered many projects and investigations (see grants list in following
section), we identify below key scientific advances that have contributed
both to this Impact Case Study on Cell Implantation, and also with
significant impact in the wider biological and cell therapy field (see
Continual monitoring of patients post-cell implantation —
has led to a better understanding of the science of cartilage repair
(Ref 1, 2) and long term clinical efficacy (Ref 2). Key researchers
1997-2013: Prof James B Richardson, Prof Sally Roberts, Dr J-H Kuiper.
Biological orthopaedic repair systems - For cases where
concomitant ligament damage or bone loss forms a significant problem in
joint repair we have developed novel biological repair systems
(composite resorbable Bilok interference screw, hydroxy-apatite
Allogran-N bone substitute) with a local company (Biocomposites; Ref 3,
4). Key researchers 1997-2013: Kuiper, Richardson.
International Scoring Benchmarks - Established an
international scoring scheme for histology as an outcome measure for
cartilage repair (ICRS II; Mainil-Varlet et al 2010 Ref 8) used
worldwide as a benchmark for clinical treatments and trials. Other
outcome measures, e.g. the Oswestry Arthroscopy Score, have been
developed for cartilage repair techniques. Key researchers 1997-2013:
Biomimetic Matrix Analogue - This technology was
patented for application in either the intervertebral disc or
intracocular lens in conjunction with Aston and Oxford Universities
(WO2009GB01006 200904). The commercial potential of the invention was
highlighted as a top three regenerative spinal technologies of the year
in the US "Best Spine Technologies of 2009" award
Nanotechnology control systems - Novel patented
technology for targeting of stem cells to injury site with controllable
activation of differentiation of mesenchymal stem cells into orthopaedic
tissues. (Patent portfolio below) A spin-out company MICA Biosystems Ltd
(Ref 5) has been formed to market the technology with early stage sales
and European funding (section 4). Key researchers: Prof Alicia J El Haj,
Prof Jon Dobson. The patented technology won the Welcome Trust Showcase
award, Lord Stafford Impact Through Innovation Award, and was
shortlisted for the Times Higher Innovation Award.
Improved stem cell production systems — Development of
new hypoxic media pre-conditioning system for improved culture of
chondrocyte precursors and stem cells in GMP conditions, HypOxyCool,
has been developed in collaboration with Ruskinn (Contact Greg May, tel
01656776044) as part of EPSRC Centre in Innovative Manufacturing of
Regenerative Medicine. The hypoxic media preconditioning unit has been
purchased by laboratories in countries throughout Europe, Asia, and the
USA. Key researcher: Dr Nicholas R Forsyth.
References to the research
Six key publications which underpin this work include:
Richardson JB et al (1999). Repair of human articular cartilage after
implantation of autologous chondrocytes. J. Bone Joint Surg. 81(6):1064-8.
(Key Paper 1)
Sivan S-S et al. (2008). Collagen turnover in normal and degenerate human
intervertebral discs as determined by the racemization of aspartic acid. J.
Biol. Chem. 283(14):8796-8801.
Smith HJ et al. (2009). Modification and validation of the Lysholm Knee
Scale to assess articular cartilage damage. Osteo. Cart. 17(1):53-8.
(Key Paper 2)
Johansson A et al. (2011). A spectroscopic approach to imaging and
quantification of cartilage lesions in human knee joints. Phys Med
Gokhale S et al (2005). Variables affecting initial stability of
impaction grafting for hip revision. Clin Orthop Relat Res.
Kanczler J et al. (2010) Controlled Differentiation of Human Bone Marrow
Stromal Cells Using Magnetic Nanoparticle Technology. Tiss. Eng. 16(10):3241-50.
(Key Paper 3)
These publications are reflected in a patent portfolio of:
El Haj AJ, Dobson JP. Culturing tissue using magnetically generated
mechanical stresses. USA Europe, China NZ, Singapore, Korea 2004147015,
El Haj AJ Dobson JP. Generation of cartilage using magnetic particles; US
patent 2010/518956 issued 30/12/2010
El Haj AJ Dobson JP - Stem cell targeting using magnetic particles US
patent 2010/596594 issued 10/2/2011
Forsyth NR. Methods and apparatuses relating to cell culture media. US
Patent 2010184219, issued 22/7/2010
Tighe BJ, Franklin V, Lydon FJ, Roberts S, Urban JPG, Sivan S.
Intervertebral disc and intraocular lens. World patent: 2009127844. Issued
Richardson, JB. System for measuring stiffness of a fractured bone. World
patent: 9535061, Issued 28/12/1995
Research grants underpinning this research:
||Title of Grant
||Cartilage Repair by Autologous Chondrocyte Transplantation (ACTIVE).
||MRC Multi-centre tria
||2004 - 2016
||BIODESIGN Rational Bioactive Materials
Design for Tissue Regeneration
||EU VII Framework
||2012 - 2016
||Landscape Award: Tissue Engineering
and Regenerative Medicine (E-TERM)
||2011 - 2017
||Arthritis Research UK Tissue
||2011 - 2016
||Arthritis Research Campaign -
||2010 - 2015
||EPSRC Centre for Innovative Manufacturing in Regenerative
Enabling the emergence of a new industry in regenerative
||2010 - 2015
||LOLA-Combining stem cell science and tissue engineering to study
the development and repair of human skeletal tissue
|El Haj, Forsyth
||Hyanji Scaffold-Hyaluronan based injectable material for tissue
||EU VII Framework
||2009 - 2013
||EPSRC Doctoral Training Centre (DTC) in Regenerative Medicine.
Joint project with Loughborough and Nottingham Universities.
||EPSRC Life Sciences Interface
||2008 - 2015
|Roberts, Kuiper Richardson
||Growing a new joint in a Human back (MY JOINT).
||EU VI Framework
||2007 - 2012
||Marie-Curie Multicentre Training Grant : Shaping the future of a
new generation of hybrid human resources for tissue engineering of
||EU VI Framework
||2005 - 2006
||Network of Excellence of Excellence in Tissue Engineering
||EU VI Framework
||2004 - 2010
||Development of a magnetic nanoparticle strategies manipulation and
activation of stem cells in vitro
||2004 - 2007
EU Partnership for Autologous Chondrocyte Implantation (EUROCELL)
||EU V Framework
||2001 - 2004
|ElHaj /Biocomp-osites Ltd
||Biomedical interactions in tissue engineering and tissue
engineering in surgical repair (BITES)
||EU V Framework
||2000 - 2003
|MICA Bio-systems Ltd
||Magnetic nanoparticles in healthcare (MagNETicFUN)
||EU VII Framework
||2013 - 2017
Details of the impact
Our research on biological and cell therapy in orthopaedics has had
direct impact on health, economics, public policy, practitioners and
Impacts on health
More than 400 patients had cell therapy in our clinics to treat their
cartilage defects (Ref 1). The treatment gave a marked improvement in the
condition in most patients, with a beneficial effect sustained for more
than eight years (Ref 2). This suggests that cell therapy can delay the
progression of osteoarthritis long enough to have a real impact on future
health costs (Ref 2).
A further 150,000 patients worldwide have benefited from our research on
biological therapies (Ref 3). The composite resorbable interference screw,
developed with Biocomposites Ltd (Keele, UK), has benefited over 60,000
patients worldwide through Stryker (Biosteon interference screw),
Arthrocare (Bilok interference screw) and Biocomposites (Bilok and
Biosteon interference screw). Use of this screw in anterior cruciate
ligament reconstruction leads to a measurable improvement in their
condition (Ref 4). Finally, over 4000 patients have benefited from our
research on bone substitute materials (Ref 3), with Biocomposites Ltd
(Keele, UK), distributed as Allogran by Endo Plus and Biocomposites. It
gives long-term benefits to patients equivalent to human allograft bone,
without the associated infection risks (Ref 4).
Worldwide sales of 125,000 composite resorbable interference screws
(Bilok, Biosteon) are reported with an associated turnover of almost
$30,000,000 (Ref 3). In addition, over 4000 units of Allogran have been
sold with an associated turnover of £450,000 (Ref 3). Sales from MICA
Biosystems are just beginning (£60,000 as of 2013) (Ref 3) with a plan for
expansion to worldwide distribution over the next 5 years (MICA MFB)
Impacts on public policy
We contributed to the advice and guidance from the National Institute for
Health and Clinical Excellence (NICE) on Autologous Chondrocyte
Implantation (ACI). For the present guideline (Ref 5), we contributed
evidence, as both a manufacturer, via our GMP-licensed lab, OsCell, and as
a commentator in the form of the Robert Jones and Agnes Hunt Orthopaedic
Hospital. For the coming guideline (expected in 2014), our GMP laboratory
will again contribute evidence (Ref 5).
Our research has put us in a position to contribute to public policy by
informing the House of Lords Science and Technology Committee on the UK
position on Regenerative Medicine (Ref 6). From October 2012 to February
2013, the House of Lords Committee held evidence sessions, to which
members of our team (Roberts and our EPSRC Manufacturing Centre with
Loughborough) contributed evidence on behalf of Arthritis Research UK and
EPSRC. The report from the House of Lords committee has led to actions
from the government on Regenerative Medicine (Ref 6).
Our research has also led to one of our team (Prof. El Haj) to advise to
the Focus Group for the Committee for Advanced Therapies (CAT) of the
European Medicines Agency (EMA), responsible for assessing the quality,
safety and efficacy of advanced-therapy medicinal products (ATMPs) and
following scientific developments in the field (Ref 6).
Our impact into policy has contributed on a Global scale with
participation (Prof El Haj) in the 2013 Regenerative Medicine World Summit
in China, a discussion forum for world leaders in regenerative medicine to
debate the barrier to adoption in regenerative medicine (Ref 7).
Impact on practitioners and professional services
Our research on Cell Therapies for Orthopaedics has led to a team member
(Prof. Roberts) being on the committee of the International Cartilage
Repair Society (ICRS) that has developed the ICRS II Visual Assessment
Scale histology scoring system for assessing the quality of human
cartilage repair (Ref 8). The scoring system is now part of the ICRS
guidelines for the design and conduct of clinical studies in articular
cartilage repair (Ref 8) and is currently being used in at least five
randomized clinical trials (Ref 9).
Members of the Keele group have been in key positions within
International societies, Scientific Advisory Boards and Research council
advisory teams in this area: President of the UK Tissue and Cell
Engineering Society (2004-9), European Chair for the International Society
for Tissue Engineering and Regenerative Medicine (2012-2016), Executive
Board of International Cartilage Repair Society (2006-2010), UKRC Stem
Cell Advisory Board (2008-2011), Regenerative Medicine Advocacy Group
(2009-), Academic Advisory Board of Institute of Physics and Engineering
in Medicine (2008-), EPSRC Strategic Advisory Teams in Cross-disciplinary
Interface, Healthcare and on the EPSRC Strategic Advisory Network, MRC
College of Experts, MRC Developmental Pathway and Clinical Science Funding
Panel, BBSRC Bioscience Industry Working Group, Deputy Chair of the BBSRC
Bioscience and Biotechnology Panel.
Sources to corroborate the impact
Ref 1: Principal Clinical Scientist, OsCell, Oswestry, SY10
Ref 2: Bhosale AM et al. (2009). Midterm to Long-Term Longitudinal
Outcome of Autologous Chondrocyte Implantation in the Knee Joint A
Multilevel Analysis. Am. J. Sports Med. 37(1 suppl), 131S-138S.
Bhandari M et al. (2012). Clinical and Economic Burden of Revision Knee
Arthroplasty. Clin Med Insights Arthritis Muscoskelet Disord.
Ref 3: Managing Director, Biocomposites Ltd, Keele, Staffordshire,
ST5 5NL, UK. (http://www.biocomposites.com/).
Mr Peter Cunliffe, MICA Biosystems Ltd, 23 Arley Road, Solihull, West
Midlands B91 1NJ, UK. Spin-out company, reg 07237355.
Ref 4: Barber FA & Boothby MH. (2007). Bilok interference
screws for anterior cruciate ligament reconstruction: clinical and
radiographic outcomes. Arthroscopy. 23(5), 476-481. Aulakh TS et
al (2009). Long-term clinical outcomes following the use of synthetic
hydroxyapatite and bone graft in impaction in revision hip arthroplasty. Biomaterials,
Ref 5: National Institute for Health and Clinical Excellence
(2005) The use of autologous chondrocyte implantation for the treatment of
cartilage defects in knee joints. Review of Technology Appraisal 16.
http://guidance.nice.org.uk/TANational Institute for Health and Clinical
Excellence (2008) Review proposal of NICE Technology Appraisal guidance
no. 89; Autologous chondrocyte implantation (ACI) for the treatment of
cartilage injury. Provisional matrix of consultees and commentators http://www.nice.org.uk/guidance/index.jsp?action=download&o=40677.
Ref 6: House of Lords Science and Technology Committee (2013)
Regenerative Medicine Report. HL Paper 23.http://www.publications.parliament.uk/pa/ld201314/ldselect/ldsctech/23/2302.htm.
Government response to the House of Lords Science and Technology Committee
inquiry into regenerative medicine. Cm 8713. http://www.parliament.uk/documents/lords-committees/science-technology/RegenerativeMedicine/GovtresponseRegenMedCm8713.pdf.
EMA, Report from CAT- Interested Parties Focus Groups (CAT-IPs FG) on
non-clinical development of ATMPs, 23 November 2012.
Ref 7: Xian Papers, World Summit on Regenerative Medicine, Xian,
China, 19-21 October 2013
Ref 8: Mainil-Varlet P et al (2010) A
new histology scoring system for the assessment of the quality of human
cartilage repair: ICRS II. Am J Sports Med. 38(5):880-90.
Mithoefer K et al (2011). Guidelines for the Design and Conduct of
Clinical Studies in Knee Articular Cartilage Repair International
Cartilage Repair Society Recommendations Based on Current Scientific
Evidence and Standards of Clinical Care. Cartilage, 2(2), 100-121.
Ref 9: NIH Trials.gov register: NCT 00414700, 01222559, 01225575,